Comparative cardiotoxicity of doxorubicin and a morpholino anthracycline derivative (KRN8602)

The toxicities of doxorubicin (DXR) and 3'-deamino-3'-morpholino-13-deoxy-10-hydroxycarcminomycin (KRN8602) were compared in perfused rat heart preparations. In addition, their toxicities in isolated myocytes as well as their abilities to cause oxidation of intracellular reduced glutathione (GSH) were evaluated. Finally, their capacities to initiate oxygen consumption and lipid peroxidation in isolated microsomes were determined. DXR caused a dramatic decrease in left ventricular pressure in the perfused hearts and a leak of lactic acid dehydrogenase (LDH) from isolated myocytes. These effects were not observed with KRN8602 at comparable concentrations although KRN8602 caused oxidation of GSH to oxidized glutathione (GSSG) in the myocytes. Both anthracyclines caused an increase in oxygen consumption and lipid peroxidation in isolated microsomes although these effects were more pronounced with KRN8602. The results of these experiments demonstrate that, despite the high capacity to redox cycle and to generate oxygen-derived oxidants, KRN8602 exhibited no measurable cardiotoxicity. The findings are consistent with a view that, if the formation of such oxidants is central to the cardiotoxicity of DXR, these substances must be formed in cellular compartments, e.g. plasma membranes, where the morpholino derivative (KRN8602) does not accumulate.